Enantioselective synthesis of cyclopropyl δ-lactonealdehydes and dodecyl-5-ene-1-yne-3-ol: Advanced intermediates of solandelactone A and B

Article abstract of DOI:10.1016/j.tetlet.2011.02.008

A stereocontrolled synthesis of cyclopropyl δ-lactonealdehydes and dodecyl-5-ene-1-yne-3-ol is accomplished with predictable absolute stereochemistry via organocatalytic and catalytic asymmetric transfer hydrogenation reactions. The salient feature of this protocol is the genesis of chirality through an organocatalytic reaction and utilized for installing a critical bifunctional trans-cyclopropane motif, which is a key segment of every representative member of the oxylipin class of natural products such as solandelactone A and B.

Full text of DOI:10.1016/j.tetlet.2011.02.008

Tetrahedron Letters 52 (2011) 1778–1782
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of cyclopropyl d-lactonealdehydes and
dodecyl-5-ene-1-yne-3-ol: advanced intermediates of solandelactone A and B
Gullapalli Kumaraswamy a, , Gajula Ramakrishna a, Balasubramanian Sridhar b
⇑
a Organic Division-III, Indian Institute of Chemical Technology, Hyderabad 500007, India
b Laboratory of X-ray crystallography, Indian Institute of Chemical Technology, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
stereocontrolled synthesis of cyclopropyl d-lactonealdehydes and dodecyl-5-ene-1-yne-3-ol is
Received 4 January 2011
Revised 29 January 2011
Accepted 2 February 2011
Available online 28 February 2011
accomplished with predictable absolute stereochemistry via organocatalytic and catalytic asymmetric
transfer hydrogenation reactions. The salient feature of this protocol is the genesis of chirality through
an organocatalytic reaction and utilized for installing a critical bifunctional trans-cyclopropane motif,
which is a key segment of every representative member of the oxylipin class of natural products such
as solandelactone A and B.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Solandelactone A and B
Cyclopropyl d-lactonealdehydes
Asymmteric hydrogenation
Organocatalytic reaction
Oxylipin family
Oxylipin family of marine origin is a source of oxygenated-
cyclopropyl containing heterocycles that have attracted a great
deal of synthetic interest owing to their significant physiological
properties as well as to the presence of appealing structural fea-
tures.1 Primarily two subfamilies of oxylipins, that is solandelac-
tones 1a–h and constanolactones 2a–b including halicholactones
3, have been identified based on the absolute configuration of
the cyclopropane ring. In 1996 solandelactones, 1a–h were isolated
as oils from the hydroid Solanderia secunda of the Korean coast.2
The solandelactones encompass a critical bifunctional trans-cyclo-
propane motif and they can be distinguished depending on the
configuration at C11 as well as the degree of saturation in the
eight-membered lactones along with a fatty acid side chain
appendage (Fig. 1).
These compounds inhibit the enzyme farnesyl transferase
which is accountable for proper expression of ras proteins found
in many types of cancer cells including pancreatic and colorectal
cancers.3
The first enantioselective total synthesis was reported by Mar-
tin et al.4 which not only led to the synthesis of solandelactone E
but also revised the stereogenic center at C11 of the originally pro-
posed structure. Ensuing to this, the total synthesis of solandelac-
tone A and B along with E and F were reported by White et al.5
Later, a spell of synthetic approaches has appeared in the litera-
ture6 for this class of compounds. Recently, we have also developed
an enantioselective total synthesis of eicosanoid and its congener,
using organocatalytic cyclopropanation, and catalytic asymmetric
transfer hydrogenation reaction as key steps.7 As
a logical
extension, in the same vein herein, we report the enantioselective
synthesis of cyclopropyl d-lactonealdehydes and dodecyl-5-ene-1-
yne-3-ol; advanced intermediates of solandelactone A and B. Our
retro synthetic analysis is illustrated in Scheme 1.
The synthesis was commenced with the reaction of enone 78
and tert-butyl bromoacetate in the presence of 10 mol % of L1
(DHQD)2Pyr and Cs2CO3 at 80 °C for 24 h by means of an earlier
O
OH
H
O
OH
H
O
5
O
11
H
7
11
H
7
HO
HO
14
4
14
4
5
20
19
20
, Solandelactone B,
19
1a, Solandelactone A,
1b
19, 20
4, 5
19, 20
4, 5
1c, Solandelactone C,
1e, Solandelactone E,
1d, Solandelactone D,
1f, Solandelactone F,
19, 20
19, 20
4, 5
4, 5
1g
, Solandelactone G,
1h, Solandelactone H,
OH
H
OH
H
O
O
6
9
12
8
5
O
HO
8
O
HO
H
H
12
15
2a
2b
, Constanolactone A (9a)
, Constanolactone B (9b)
3, Halicholactone
⇑
Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27193275.
E-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
Figure 1. Oxilypin family.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.008

G. Kumaraswamy et al. / Tetrahedron Letters 52 (2011) 1778–1782
1779
Catalytic Noyori's reduction
O
Catalytic Gaunt cyclopropanation
OH
H
O
Catalytic Noyori's reduction
8
11
H
7
10
HO
14
1a
O
O
H
O
HO
+
H
H
4
8
SiMe3
O
HO
H
MeO
N
OH
H
Me
OTBDPS
9
5
O
Me3Si
+
O
O
10
MeO
11
Br
+
OTBDPS
N
7
6
Me
Scheme 1. Retrosynthesis.
O
MeO
O
Br
L1
(10 mol%)
N
O
Cs2CO3 , CH3CN
slow addition, 80 o
Me
6
H
MeO
N
O
C
+
H
Me
24 h
88%
OTBDPS
OTBDPS
12
7
L2
(20 mol%)
Cs2CO3 , CH3CN
slow addition, 80 oC,
O
H
MeO
7
6
+
N
O
H
Me
24 h
85%
OTBDPS
ent-12
N
Ph
N
O
O
OMe
N
N
MeO
N
N
OMe
OBn
Ph
(DHQD)2Pyr,
N
N
L1
L2
Quinine 9-O-Benzylether,
Scheme 2. Catalytic cyclopropanation.
developed protocol. To our dismay, only a trace amount of the re-
quired product 12 was observed. After considerable experimenta-
tion, using 2-bromo-N,O-dimethylacetamide 6 in place of tert-
butyl bromoacetate under otherwise identical conditions led to
the formation of cyclopropane compound 12 in 88% isolated yield.
The enantiomer ent-12 was prepared employing 10 mol % of ben-
zyl ether quinine ligand L2 in place of L1 under similar conditions
as above resulted in 85% yield. The enantioselectivity and relative
configuration were assigned by analogy7b (Scheme 2).
Having both enantiomers in hand, we then evaluated the reduc-
tion of keto group in cyclopropane compound 12 by way of cata-
lytic asymmetric transfer hydrogenation.9 The reduction of 12
with 1 mol % of the chiral Ru catalyst, L3 and 5 mol % of K2CO3 in
2-propanol at 80 °C for 6 h generated the required product 5 in
85% yield. The diastereomeric ratio was ascertained by chiral HPLC
(OD-H column, 20% isopropanol in hexane, flow rate 0.5 mL/min)
and found to be 9.5:0.5. As expected, using complementary ligand
L4 under otherwise identical conditions led to the diastereomeric
alcohol 5a with considerable yield (88%). Similarly, subjecting
ent-12 to reduction by 1 mol % of the Ru catalyst, and L3 ligand fur-
nished the ent-5a in good yield with 9.6:0.4 diastereomeric ratio
which was analyzed by chiral HPLC (OD-H column, 20% isopropa-
nol in hexane, flow rate 0.5 mL/min). The absolute stereochemistry
of the newly formed stereogenic center was assigned based on
Noyori0s protocol9 that is R,R-diamine-Ru catalyst induces
R-configuration (as in 5, ent-5a), while S,S-diamine-Ru generates

1780
G. Kumaraswamy et al. / Tetrahedron Letters 52 (2011) 1778–1782
S-configuration (5a). These results indicate that the asymmetric
reduction proceeded with good facial selectivity, as a result of re-
agent control with little or no influence due to the substrate
(Scheme 3).
Having prepared the requisite cyclopropyl alcohols 5, 5a, and
ent-5a, we then transformed them into their respective cyclopro-
pyl d-lactone aldehydes independently. To this end, the secondary
hydroxyl group of cyclopropyl alcohol 13 was converted to TES-
ether 13 and subsequent reduction of Weinreb amide of 13 with
DIBAL-H at ꢀ78 °C in CH2Cl2 resulted in the crude aldehyde, which
was further subjected to a reduction (NaBH4 in MeOH at 0 °C for
1 h) to give alcohol 14 in 78% isolated yield over two steps. The pri-
mary alcohol of compound 14 was protected as its trityl ether to
yield 15 in 92% yield. Further, the fluoride ion initiated cleavage
of TES and TBDPS of 15 led to the diol 16 in 90% yield (Scheme 4).
Our endeavor for selective oxidation of the primary alcohol of
16 to aldehyde, concomitant hemiacetal formation and further oxi-
dation under Ley condition strategy failed to give the anticipated
cyclopropyl d-lactone 19.7b Alternatively, we envisioned that the
oxidation of primary alcohol to aldehyde and further oxidation to
corresponding acid followed by Yamaguchi lactonization could
lead to cyclopropyl d-lactone 19. Accordingly, the diol 16 treated
with TEMPO, BAIB in CH2Cl2 at room temperature for 1 h afforded
aldehyde 17 which was immediately subjected to Pinnick oxida-
tion (NaClO2 and 20% aq NaH2PO4 in t-BuOH) provided cleanly
the mono-hydroxy acid 18 in 93% yield. The product 18 smoothly
underwent lactonization under Yamaguchi condition10 to furnish
the eight-membered lactone 19 in 94% yield. Following the depro-
tection of trityl group using 1 M solution of BCl3 in CH2Cl2 at
ꢀ30 °C for 30 min secured the hydroxy cyclopropane compound
2011 in 85% yield. Upon oxidation under Ley12 conditions, the
alcohol 20 resulted in the desired segment cyclopropyl d-lactone
aldehyde 4 in 79% yield (Scheme 5). The spectral and chirooptical
L3 (1mol%)
O
H
MeO
K2CO3, IPA
N
OH
80 oC, 6 h
85%
Me
H
OTBDPS
OTBDPS
5 (dr = 9.5:0.5)
12
L4 (1mol%)
O
H
MeO
K2CO3, IPA
N
OH
80 oC, 6 h
88%
H
Me
5a
O
L3 (1mol%)
K2CO3, IPA
H
MeO
N
OH
ent-12
H
Me
80 oC, 6 h
86%
OTBDPS
ent-5a (dr = 9.6:0.4)
H
H
N
Ph
N
Ph
Ph
Ru
N
Ru
N
Ph
Ts
Ts
L4
L3
Scheme 3. Catalytic asymmetric transfer hydrogenation reaction.
O
i) DIBAL-H
TESOTf
MeO
DCM, -78 oC, 2 h
H
2, 6-lutidine
N
OTES
5
DCM, 0 oC
45 min, 92%
ii) NaBH4, MeOH
H
Me
0 oC, 1 h
OTBDPS
TrO
13
78% over 2 steps
H
H
HO
OTES
TrCl, Et3N
OTES
H
H
DCM, TBAI
0 oC to rt, 3 h
92%
OTBDPS
TrO
OTBDPS
14
15
H
OH
TBAF, THF
H
0 oC to rt, 1 h
90%
OH
16
Scheme 4. Synthesis of diol.
H
NaH2PO4, NaClO2
TEMPO, BIAB
TrO
OH
16
H
t-BuOH, 20 oC, 1 h
93%
DCM, rt, 1 h
95%
H
17
O
O
H
H
i) 2,4,6-trichloro
benzoyl chloride
TrO
OH
O
1M BCl3, DCM
H
TrO
-30 oC, 30 min
85%
OH
Et3N, DMAP
THF, 1 h
ii) toluene, reflux
4 h, 94%
H
18
19
O
O
H
O
O
H
O
TPAP, NMO
4Ao MS
DCM, rt, 20min.
O
HO
H
H
H
79%
20
4
Scheme 5. Synthesis of cyclopropyl d-lactone aldehyde.

G. Kumaraswamy et al. / Tetrahedron Letters 52 (2011) 1778–1782
1781
O
O
O
H
H
O
O
TrO
H
5a
H
H
19a
4a
O
O
H
O
ent-5a
H
H
ent-4a
Scheme 6. Synthesis of cyclopropyl d-lactone aldehyde.
i) DMP, CH2Cl2
0 oC to rt 1h
i) DMP, CH 2Cl2
0 oC to rt 1h
SiMe3
HO
21
ii) Cat L4 (1 mol%)
Et3N:HCOOH (5:2)
EtOAc, rt, 3h
ii) n-BuLi, 11
-78 oC, 2h
95% over 2 steps
( )-9
95% over 2 steps
SiMe3
i) TBSOTf, 2,6-lutidine
CH2Cl2, 0 oC, 2h
HO
TBSO
ii) K2CO3, MeOH
rt, 12h
92% over 2 steps
(-)-9
22
K2CO3, MeOH
rt, 12h, 96%
8
Scheme 7. Synthesis of dodecyl-5-ene-1-yne-3-ol.
data were in full agreement with the data reported in the litera-
ture6a,13 thus, the absolute configuration of the newly formed ste-
reogenic centers in 4 was assigned as 7R, 8R, and 10R.
Similarly, the aldehyde 4a and ent-4a were synthesized from 5a
and ent-5a, respectively, by repeating the above reaction sequence
(Scheme 6).
(1 equiv of K2CO3 in MeOH at rt for 12 h) to afford the acetylenic
compound 22 in 92% yield. The spectral data and the optical rota-
tion value (½a 2D3
ꢁ
ꢀ27.0 (c 0.5, CCl4) {lit 16
½
a 2D3
+28.5 (c 0.02, CCl4) for
ꢁ
opposite isomer} were in full agreement with reported data found
in the literature.16 Based on this, the absolute configuration of
newly formed stereogenic center was assigned as S. The TMS group
of compound (ꢀ)-9 was removed under basic conditions and also
resulted in the hydroxyl acetylenic compound 8 in 96% yield
(Scheme 7).
The absolute configuration of the trityl ether compound 19a
was assigned as 7S, 8R, and 10R based on single X-ray crystallogra-
phy (CCDC reference no. 804794 [see the Supporting information]).
This in turn corroborates for the assigned absolute configurations
in both organocatalytic cyclopropanation and catalytic asymmetric
transfer hydrogenation reactions. Since ent-4a is an enantiomer to
4a, as a result the absolute configuration was assigned as 7R, 8S,
and 10S.
On the other hand, we decided to take on asymmetric transfer
hydrogenation (ATH) to install the stereogenic center present in
another segment 8. Consequently, the synthesis commenced with
commercially available cis-3-nonenol 21. Dess–Martin oxidation14
of 21 resulted in the aldehyde 10, and subsequent treatment with
lithiated TMS-acetylide furnished the racemic alcohol ( )-9
(95%).Then, the secondary alcohol ( )-9 was oxidized using Dess–
Martin reagent14 to afford the acetylenic keto compound15 and
the crude residue was directly subjected to asymmetric transfer
hydrogenation employing (S,S)-Ru catalyst L4 and the Et3N:HCOOH
(5:2) azeotropic mixture as a hydrogen donor in EtOAc at rt for 3 h
furnished the desired alcohol (ꢀ)-9 (95% yield over two steps).
Next, the secondary alcohol of (ꢀ)-9 was protected as its TBS ether
in the presence of TBSOTf and 2,6-lutidine in CH2Cl2 at 0 °C for 2 h.
Finally, the TMS group was removed under basic conditions
In conclusion, we have succeeded in developing a catalytic
enantioselective unified strategy for an enantioselective synthesis
of cyclopropyl d-lactonealdehydes 4, 4a, ent-4a and dodecyl-5-
ene-1-yne-3-ol, 8 which are critical intermediates of the oxylipin
class of natural products. To the best of our knowledge, the synthe-
ses of 4a and ent-4a are described here for the first time. The sali-
ent features of this protocol are (i) the origin of chirality through an
organocatalytic reaction, (ii) the cyclopropanes can be produced as
either enantiomer employing catalytic amount of quinine or quin-
idine based alkaloids, and (iii) the application of Noyori0s CATHy
reaction that could lead to the synthesis of C(7) and C(14) epimeric
alcohols which in turn would make possible the synthesis of each
representative member of the oxylipin family. Further, work is un-
der progress for the total synthesis of solandelactones 1a–h, and
the results will be published elsewhere in due course.
Acknowledgments
We are grateful to Dr. J.S. Yadav, Director, IICT, for his constant
encouragement. Financial support was provided by the DST, New

1782
G. Kumaraswamy et al. / Tetrahedron Letters 52 (2011) 1778–1782
8. The enone 7 was conveniently prepared in four steps from 1,7-heptane diol, see
Supporting information.
9. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997,
119, 8738; (b) Haack, K.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. 1997, 36, 285.
Delhi, India (Grant No: SR/SI/OC-12/2007) and CSIR (New Delhi) is
gratefully acknowledged for awarding the fellowship to GRK.
Thanks are also due to Dr. G.V.M. Sharma for his support.
10. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
Supplementary data
11. (R)-8-((1R,2R)-2-(hydroxymethyl)cyclopropyl)oxocan-2-one (20): To
a stirred
solution of lactone 19 (0.6 g, 1.32 mmol) in CH2Cl2 (40 mL) was added BCl3
(0.096 mL, 0.79 mmol) 1 M solution in CH2Cl2 at ꢀ30 °C over 30 min. The
resulting reaction mixture was stirred for 30 min at the same temperature. The
reaction mixture was quenched with MeOH (10 mL) and saturated NaHCO3
solution. The organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (3 ꢂ 20 mL). The combined organic layers were dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The crude
residue was purified by silica gel column chromatography (40% EtOAc in
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.008.
References and notes
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hexane) to obtain compound 20 as colour less oil (0.22 g, 85%). ½a D23
ꢁ
: + 4.0 (c
1.5, CHCl3); IR (neat): mmax 3421, 2924, 2855, 1715, 1458, 1235, 1057,
801 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.08 (q, J = 6.9 Hz, 1H), 3.56 (dd,
;
J = 6.6, 10.9 Hz, 1H), 3.45 (dd, J = 6.9, 10.7 Hz, 1H), 2.45 (t, J = 6.2 Hz, 2H), 1.88–
1.52 (m, 5H), 1.14–1.00 (m, 2H), 0.92–0.81 (m, 3H), 0.72–0.65 (m, 1H), 0.59–
0.53 (m, 1H); 13C NMR (75 MHz, CDCl3): d 176.0, 81.6, 66.0, 37.1, 32.6, 29.7,
26.4, 24.1, 21.4, 19.3, 8.5; MS (ESI): m/z 221 [M+Na]+; HRMS (ESI): m/z
221.1144 (calcd for C11H18O3Na: 221.1153).
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molecular sieves (0.48 g), N-methylmorpholine N-oxide (0.089 g, 0.75 mmol)
and tetrapropylammonium perruthenate (0.035 g, 0.1 mmol) at the same time.
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of solvent resulted in
a residue aldehyde 4, which upon flash column
chromatography over silicagel (30% EtOAc in hexane) gave the product as
colourless oil (77 mg, 79%). ½a D23
ꢁ
: ꢀ32.0 (c = 0.5, CHCl3); IR (neat): mmax 2925,
2855, 1708, 1515, 1459, 1235, 1062, 1008 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
9.17 (d, J = 5.2 Hz, 1H), 4.41 (q, J = 6.0 Hz, 1H), 2.44 (dt, J = 1.5, 6.0, 7.5 Hz, 2H),
1.94–1.88 (m, 2H), 1.85–1.76 (m, 4H), 1.71–1.50 (m, 4H), 1.36–1.28 (m, 2H);
13C NMR (75 MHz, CDCl3): d 199.9, 176.3, 78.2, 37.0, 33.0, 29.2, 27.2, 26.5, 25.4,
24.1, 12.0; MS (ESI): m/z 219 [M+Na]+; HRMS (ESI): m/z 219.0990 (calcd for
C
11H16O3Na: 219.0997).
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hence crude residue was directly subjected to asymmetric transfer
hydrogenation.
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